Doi:10.1016/j.ijgo.2004.04.004

International Journal of Gynecology and Obstetrics 86 (2004) 351–357
Human chorionic gonadotrophin and progesterone levels in
G. Condousa,*, C. Lub, S.V. Van Huffelb, D. Timmermanc, T. Bournea
Pregnancy, Gynaecological Ultrasound and MAS Unit, Department of Obstetrics & Gynaecology,St George’s Hospital Medical School, Cranmere Terrace, London SW17 0RE, UKof Electrical Engineering (ESAT), K.U.Leuven, Belgiumof Obstetrics and Gynaecology, University Hospital Gasthuisberg, K.U.Leuven, Belgium
Received 26 January 2004; received in revised form 12 April 2004; accepted 12 April 2004
AbstractObjective: To evaluate accuracy, user variability and impact of experience on the use of serum hCG and progesterone
in women who have a pregnancy of unknown location (PUL’s). Materials and methods: This was a retrospectivestudy. Presenting 1932 consecutive women to an Early Pregnancy Unit had a transvaginal scan. The location of thepregnancy could not be found in 189women (Pregnancy of unknown location, PUL), and so blood was taken tomeasure serum hCG and progesterone at presentation and subsequently after 48 h, according to the protocol. Allwomen were monitored at regular intervals until the final outcome was known, which was a failing PUL, a viable orfailing intra-uterine pregnancy, an ectopic pregnancy or a persisting PUL. The final study group comprised 185 PUL,as four cases of persisting PUL were treated and excluded from the analysis. Five investigators assessed the hormonaldata independently. The investigator’s experience as defined by the number of years working in obstetrics andgynecology ranged from 2 to 15 years. Each investigator knew the women were clinically stable and that the scanresult was consistent with a PUL, i.e. there were no signs of intra- or extra-uterine pregnancy, and there was nohemoperitoneum on TVS. When assessing the PUL’s, each investigator was given the hormonal results at time 0 and48 h for serum hCG and progesterone and asked to classify the PUL’s as failing PUL’s, immediately viable intra-uterine PUL’s and ectopic PUL’s. No other clinical information about the women was made available. Results:Complete data 185 women (89%): 102 failing PUL’s, 63 immediately viable intra-uterine PUL’s and 20 ectopicPUL’s (total 185). The most experienced investigator obtained the best accuracy 163y185 (88.1%); not significantlydifferent from those obtained by less experienced investigators (range 85.9–87.6%). Mean correct classification offailing PUL and immediately viable intra-uterine PUL’s was 93% (range 89–95%); corresponding value for ectopicPUL’s was 42% (range 25–60%). Agreement between observers for classification of failing PUL’s and immediatelyviable intra-uterine PUL’s was almost perfect (Cohen’s kappa 0.86–0.90), whereas the value for ectopic PUL’s groupwas fair to moderate (Cohen’s kappa 0.39–0.67). All 5 investigators misdiagnosed same 35% of ectopic PUL’s.Conclusions: Serum hCG and progesterone levels at defined times can be used to predict the immediate viability of
*Corresponding author. Tel.: q44-208-725-0050; fax: q44-208-725-0094.E-mail address: [email protected] (G. Condous).
0020-7292/04/$30.00 ᮊ 2004 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rightsreserved.doi:10.1016/j.ijgo.2004.04.004
G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357
a PUL, but cannot be used reliably to predict its location. Clinical experience does not significantly improve theability to assess PUL outcome.
ᮊ 2004 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.Keywords: Ectopic pregnancy; Human chorionic gonadotrophin; Progesterone; Interuser variability; Transvaginal sonography;Pregnancy of unknown location
1. Introduction
in 8–31% of women who present to an EarlyPregnancy Unit (EPU)
The diagnosis of ectopic pregnancy should be
Traditionally the discriminatory zone or level of
based on the positive visualization of an extra-
serum hCG above which an intra-uterine pregnan-
uterine pregnancy outside the uterus, rather than
cy should be visualized has been used to predict
the absence of an intrauterine pregnancy. Between
the likelihood of an ectopic pregnancy in women
87 and 93% of ectopic pregnancies may be visu-
alized using transvaginal sonography (TVS)
over a 48 h period is also utilized to predict the
Standard algorithms for the diagnosis of ectopic
pregnancy in the absence of the positive visuali-
ments of serum progesterone have been shown to
zation of an extra-uterine pregnancy utilize serum
be useful in evaluating the chances of early preg-
hCG and progesterone measurements with ancil-
nancy failure. According to previously published
lary aids that include ultrasound imaging, laparos-
data, a baseline serum progesterone level of -20
copy and diagnostic dilatation and curettage. In
nmolyl can be used to identify a failing PUL with
our unit we rely primarily on ultrasound, with
90.8% of ectopic pregnancies visualized using
are ectopic pregnancies and it is the detection of
transvaginal sonography (TVS) prior to surgery
women in this group that poses the greatest chal-
This means that only a few ectopic pregnan-
lenge. To our knowledge there are no data to
cies will fall into the pregnancy of unknown
examine interuser variation of the interpretation of
location (PUL) category. It is this group that we
these hormonal indices and observer experience
on the accurate classification of PUL. Hence the
With the introduction of Early Pregnancy Units
objective of our study was to evaluate the accuracy,
and the use of high-resolution transvaginal probes,
interuser variation and impact of clinical experi-
ectopic pregnancies are detected at a relatively
ence on the interpretation of measurements of
asymptomatic stage and more treatment options
serum hormones for the assessment of women
have become available. However, as women have
been encouraged to present earlier in pregnancy,the number of women presenting where a pregnan-
2. Materials and methods
cy is not seen either inside or outside the uterushas increased. These cases are classified as preg-
Presenting 1932 consecutive women presenting
nancies of unknown location (PUL). The estab-
to the EPU at St George’s Hospital, London
lished hormonal criteria for the diagnosis of
between June 2001 and March 2002 were studied.
ectopic pregnancy have been based on data col-
All women had a transvaginal scan with a 5 MHz
lected from pregnancies associated with abdominal
probe (Aloka SSD 900 or 2000, Keymed Ltd.,
pain and abnormal transvaginal bleeding and not
Southend, UK and Aloka Co. Ltd., Tokyo, Japan).
from relatively asymptomatic women. Consequent-
The location of the pregnancy could not be
ly new diagnostic criteria are being developed and
found in 189women, and so blood was taken to
tested in order to detect ectopic pregnancies in
measure serum human chorionic gonadotrophin
women with a PUL whilst avoiding intervention
(hCG, World Health Organization, Third Interna-
in early intra-uterine pregnancies. A PUL is found
tional Reference Preparation 75y537) and proges-
G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357
terone (Roche Elecsys 2010 Progesterone II test)
was a high index of suspicion based on sympto-
levels using an automated electrochemiluminesc-
matology, clinical findings and sub-optimal rises
ence immunoassay (‘ECLIA’). These samples
of serial serum hCG levels, a laparoscopy was
were measured at presentation and subsequently
performed with or without an evacuation of the
after 48 h, according to the protocol.
uterus. Those women who had negative findings
A PUL was defined on the basis of a serum
on TVS and negative findings on laparoscopy, but
hCG level )5 Uyl and the absence of signs of
their serum hCG levels had reached a plateau were
either an intra- or extra-uterine pregnancy or
given methotrexate. All women were followed up
retained products of conception by TVS. All wom-
until a final diagnosis was established.
en were monitored at regular intervals until thefinal outcome was known, which was a failing
3. Study design
PUL, a viable or failing intra-uterine pregnancy,an ectopic pregnancy or a persisting PUL. The
The study was retrospective. Five investigators
final study group comprised 185 PUL, as four
assessed the hormonal data independently. The
cases of persisting PUL were treated and excluded
investigator’s experience as defined by the number
of years working in obstetrics and gynecology
Indications for sonography included non-specif-
ranged from 2 to 15 years. Each investigator knew
ic lower abdominal pain, with or without vaginal
the women were clinically stable and had a scan
bleeding, poor obstetric history (previous miscar-
result consistent with a PUL, i.e. there were no
riage or ectopic pregnancy) or to determine ges-
signs of intra- or extra-uterine pregnancy, and there
was no haemoperitoneum on TVS. When assessing
the PUL, each investigator was given the hormonal
made in the following way. If the initial serum
results at time 0 and 48 h for serum hCG and
progesterone level was -20 nmolyl, the women
progesterone. No other clinical information about
were classified as having a failing PUL. Sponta-
neous resolution of the pregnancy was defined as
Each investigator used accepted current criteria
a decrease in the serum hCG level to -5 Uyl
for the prediction of failing PUL, immediately
with the disappearance of symptoms. The location
viable intra-uterine PUL and ectopic PUL. A low
of these failing pregnancies remained unknown.
serum progesterone at time 0 h was used to predict
Serum hCG levels were repeated within 7 days to
failing PUL’s; a serum hCG rise G66% over 48
h was used to predict immediately viable intra-
If the serum hCG rise over the 48 h period was
uterine PUL’s; and either a discriminatory zone
G66%, for the purposes of this study, the women
G1500 Uyl andyor a sub-optimally rising serum
were considered to have an immediately viable
hCG over 48 h was used to predict ectopic PUL’s.
intra-uterine PUL and were rescanned 2 weeks
Each investigator was asked to apply these algo-
later to confirm the diagnosis. When a gestation
rithms to the raw hormonal data as they would in
sac was seen, a further scan was performed 2
normal clinical practice. The investigators were
weeks later to confirm the presence or absence of
blind to the final classification of the PUL and the
fetal cardiac activity. Those with no cardiac activity
at the rescan were defined as being non-viablepregnancies.
Women who did not fall into either category
were reviewed every 48 h until a diagnosis was
Accuracy was defined as the sum of the cor-
made by sonography. If an EP was visualized on
rectly diagnosed ectopic PUL’s, failing PUL’s and
TVS, the women were counselled appropriately
immediately viable intra-uterine PUL’s divided by
and offered either expectant management, medical
the total number of cases studied (ns185),
management in the form of parenteral methotrexate
expressed as a percentage. The interuser agreement
or surgery. If an EP was not visualized, but there
was evaluated with kappa statistics, which give
G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357
the chance-corrected measures of agreement. A
Agreements between observer A and observers B–E
kappa statistic of 1.0 suggests complete agreement.Kappa statistics of 0.81–1.0 indicate almost perfect
agreement, 0.61–0.8 substantial agreement, 0.41–
0.6 moderate agreement and 0.21–0.4 fair agree-
ment. A kappa statistic of 0 suggests that the same
degree of agreement would be expected by chance
alone Cohen’s kappa was used to analyze the
agreement between two observers The mod-ified method of Fleiss was used to assess the
Failing PUL’s and immediately viable intra-uterine PUL’s
agreement among multiple observers at the one
computed individually for each PUL subclass and
an overall composite kappa statistic across allsubclasses. A P value of less than 0.05 wasregarded as significant. Statistical analysis was
high for failing PUL’s (93.4%, range 89.2–99%)
performed using the SAS software package, ver-
(90.8%, range 87.3–93.7%). Conversely, the meanaccuracy for the classification of ectopic PUL’s
4. Results
was poor by all observers (42%, range 25–60)(see .
The final clinical outcome for the 185 PUL
were: 165 non-ectopic pregnancies (102 failingPUL (55.1%) and 63 intrauterine pregnancies
(34.1%) and 20 ectopic pregnancies (10.8%).
observer (A) was compared to the other observers
Of the 63 immediately viable intra-uterine preg-
nancies, 51 were viable and 12 were non-viable
observer A and the others for the diagnosis of
non-ectopic PUL’s is shown in Similarlythe agreement between observer A and the others
4.2. Diagnostic accuracy of different observers
for the diagnosis of ectopic PUL’s is shown inThere was almost perfect agreement
The most experienced observer (A) obtained an
between observer A and the other observers in the
overall accuracy of 88.1%, but this value was not
classification of the group containing failing PUL’s
significantly different from the other observers
and immediately viable intra-uterine PUL’s (Coh-
(range 85.9–87.6%). The mean classification of
en’s kappa 0.858–0.899). This finding is in con-
non-ectopic pregnancies by all observers was very
trast to the classification of the ectopic PUL group,
Table 1Diagnostic accuracy of each observer
G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357
whether interpretation of recorded serum hCG and
progesterone levels could be used to classify PULas ectopic PUL’s or failing PUL’s or immediately
viable intra-uterine PUL’s. In women with a PUL
these are the criteria on which management is
based. A further aim was to evaluate the influence
of experience on overall test performance.
Gestational age and endometrial thickness have
not been shown to be useful in the diagnosis ofectopic pregnancy in women with a PUL
in which there was only fair to substantial agree-
Thus, in this study, the investigators were not
ment between the observers (Cohen’s kappa
provided with additional demographic or ultrason-
0.394–0.672). In 75.1% of PUL all five observers
made a correct classification. However, whilst all
According to our data, current algorithms for
five correctly classified 88.3% of failing PUL’s
the diagnosis of failing PUL’s (low initial serum
and 80.7% of immediately viable intra-uterine
progesterone) and immediately viable intrauterine
PUL’s, in no cases of ectopic pregnancy did all
PUL’s (‘doubling’ serum hCG) are extremely acc-
five observers agree. In 4.9% of the PUL, all five
urate. The almost perfect interuser agreement in
observers made an incorrect classification. In 35%
the non-ectopic pregnancy group probably means
of ectopic PUL’s all five observers missed the
that most cases of failing PUL and immediately
viable intra-uterine PUL’s are in fact quite easy to
Similar information was also given by the kappa
characterize on the basis of serum hormone levels.
statistics for agreement among multiple observers.
Conversely, a discriminatory zone )1500 Uyl
andyor sub-optimally rising serum hCG levels for
classes assigned by each observer and the kappa
the diagnosis of ectopic PUL’s are poor diagnostic
statistics for individual and overall PUL subclass-
tests. The fair to substantial agreement between
es. Kappa statistics were highest (0.861 and 0.892)
the observers demonstrates the difficulty in clas-
for the high-frequency subclasses of failing PUL’s
sifying the ectopic group of PUL’s. This highlights
and immediately viable intra-uterine PUL’s. The
the need for improved diagnostic tests for the
kappa statistic for the low-frequency category of
If we consider the ectopic PUL group (20y185,
10.8%), which pose the greatest threat to women
5. Discussion
in the first trimester, the results are in fact quitediscouraging. All clinicians failed to diagnose
The distinction between PUL’s that are devel-
ectopic PUL’s in a high percentage of cases. On
oping ectopic pregnancies, early intra-uterine preg-
average, 58% (range 40–75%) of the women with
nancies and failing PUL’s based on the inter-
early ectopic PUL’s were misclassified as failing
pretation of hormonal markers is the most difficult
PUL and would have been managed inappropriate-
diagnostic problem seen in Early Pregnancy Units
(EPU). Although the vast majority will be failing
The ectopic PUL’s were misclassified in the
PUL’s and early intra-uterine pregnancies, it is the
following way. Observer A classified 45% of the
group of women with an early ectopic pregnancy
ectopic PUL’s as failing PUL and 15% as imme-
(approx. 10%) too early to visualize that pose the
diately viable intra-uterine PUL’s. Observer B
greatest concern To date, there are no pub-
classified 55% of the ectopic PUL’s as failing
lished data examining interuser variation of the
PUL and 20% as immediately viable intra-uterine
interpretation of hormonal indices and observer
PUL’s. Observer C classified 35% of the ectopic
experience on the accurate classification of PUL.
PUL’s as failing PUL and 5% as immediately
The primary aim of this study was to assess
viable intra-uterine PUL’s. Observer D classified
G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357
30% of the ectopic PUL’s as failing PUL and 10%
Acknowledgments
as immediately viable intra-uterine PUL’s. Observ-er E classified 70% of the ectopic PUL’s as failing
This research was supported by interdisciplinary
PUL and 5% as immediately viable intra-uterine
research grants of the research council of the
PUL’s. The majority of ectopic PUL’s were mis-
Katholieke Universiteit Leuven, Belgium (IDOy
classified as failing PUL’s. This is not surprising
99y03 and IDOy02y009projects), by the Belgian
as 10y20 ectopic PUL’s had initial serum proges-
Programme on Interuniversity Poles of Attraction
terone -20 nmolyl. This misclassification is a
(IUAP Phase V-22) and the Concerted Action
potential clinical problem as seven is this group
Project MEFISTO-666 of the Flemish Community.
required surgical intervention. Although the pres-
Chuan Lu is supported by a KU Leuven Ph.D.
ent report is of a retrospective analysis, it high-
lights the need for the development of newermodels that are not only well accepted universally,
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Technical Report #9 Adjuvant Multi-agent Chemotherapy and Tamoxifen Usage Trends for Breast Cancer in the United States Departments of Pathology1 and Surgery2, Massachusetts General Hospital and the Department of Pathology3, Harvard Medical School, Boston, Massachusetts Correspondence to James S. Michaelson Ph.D., Division of Surgical Oncology, Cox Building Room 626, Massa